Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling

The molecular mechanisms mediating the anti-proliferative effects of the murine anti-HER2 monoclonal antibody (4D5) were investigated in HER2-overexpressing human carcinoma cell lines. Treatment with 4D5 resulted in a dramatic accumulation of BT-474 breast carcinoma cells in Gl; concomitant with reduced expression of proteins involved in sequestration of the cyclin E/Cdk2 inhibitor protein p27, increased association of p27 with Cdk2 complexes and Cdk2 inactivation. No equivalent effects were observed in BT-474 cells treated with a control, non-inhibitory HER2 monoclonal antibody (FRP5) or in a HER2-overexpressing cell line insensitive to 4D5 treatment (MKN7 gastric carcinoma cells), confirming the relationship between these molecular changes and 4D5-mediated inhibition of proliferation. Increased p27 expression was also observed in 4D5-treated BT-474 cells; however an antisense approach demonstrated that this increase was not required for Cdk2 inactivation or establishment of the Gl block. These data suggest that 4D5 interferes with HER2 receptor signaling, resulting in downregulation of proteins involved in p27 sequestration. This causes release of p27, allowing binding and inhibition of cyclin E/Cdk2 complexes and inhibition of Gl/S progression. This model was confirmed using a second 4D5-sensitive, HER2-overexpressing breast tumor line (SKBR3), and suggests that the dependency of a given tumor cell on elevated HER2-receptor signaling for the maintenance of p27 sequestration proteins may determine the clinical response to treatment with the humanized anti-HER2 monoclonal antibody Herceptin® (trastuzumab

Pleasure and pedagogy: the consumption of DVD add-ons among Irish teenagers

This article addresses the issue of young people and media use in the digital age, more specifically the interconnection between new media pleasures and pedagogy as they relate to the consumption of DVD add-ons. Arguing against the view of new media as having predominantly detrimental effects on young people, the authors claim that new media can enable young people to develop media literacy skills and are of the view that media literacy strategies must be based on an understanding and legitimating of young people's use patterns and pleasures. The discussion is based on a pilot research project on the use patterns and pleasures of use with a sample of Irish teenagers. They found that DVDs were used predominantly in the home context, and that, while there was variability in use between the groups, overall they developed critical literacy skills and competences which were interwoven into their social life and projects of identity construction. The authors suggest that these findings could be used to develop DVDs and their add-on features as a learning resource in the more formal educational setting and they go on to outline the potential teaching benefits of their use across a range of pedagogical areas

Dugesia species

25 p. : ill. ; 24 cm.Includes bibliographical references (p. 21-24)

Distribution and abundance of fish and crayfish in a Waikato stream in relation to basin area

The aim of this study was to relate the longitudinal distribution of fish and crayfish to increasing basin area and physical site characteristics in the Mangaotama Stream, Waikato region, North Island, New Zealand. Fish and crayfish were captured with two-pass removal electroshocking at 11 sites located in hill-country with pasture, native forest, and mixed land uses within the 21.6 km2 basin. Number of fish species and lineal biomass of fish increased with increasing basin area, but barriers to upstream fish migration also influenced fish distribution; only climbing and non-migratory species were present above a series of small waterfalls. Fish biomass increased in direct proportion to stream width, suggesting that fish used much of the available channel, and stream width was closely related to basin area. Conversely, the abundance of crayfish was related to the amount of edge habitat, and therefore crayfish did not increase in abundance as basin area increased. Densities of all fish species combined ranged from 17 to 459 fish 100 m-2, and biomass ranged from 14 to 206 g m-2. Eels dominated the fish assemblages, comprising 85-100% of the total biomass; longfinned eels the majority of the biomass at most sites. Despite the open access of the lower sites to introduced brown trout, native species dominated all the fish communities sampled

The evolutionary status of the semiregular variable QYSge

Repeated spectroscopic observations made with the 6m telescope of yielded new data on the radial-velocity variability of the anomalous yellow supergiant QYSge. The strongest and most peculiar feature in its spectrum is the complex profile of NaI D lines, which contains a narrow and a very wide emission components. The wide emission component can be seen to extend from -170 to +120 km/s, and at its central part it is cut by an absorption feature, which, in turn, is split into two subcomponents by a narrow (16km/s at r=2.5) emission peak. An analysis of all the Vr values leads us to adopt for the star a systemic velocity of Vr=-21.1 km/s, which corresponds to the position of the narrow emission component of NaI. The locations of emission-line features of NaI D lines are invariable, which point to their formation in regions that are external to the supergiant's photosphere. Differential line shifts of about 10km/s are revealed. The absorption lines in the spectrum of QYSge have a substantial width of FWHM~45 km/s. The method of model atmospheres is used to determine the following parameters: Teff=6250K, lg g=2.0, and microturbulence Vt=4.5km/s. The metallicity of the star is found to be somewhat higher than the solar one with an average overabundance of iron-peak elements of [Met/H]=+0.20. The star is found to be slightly overabundant in carbon and nitrogen, [C/Fe]=+0.25, [N/Fe]=+0.27. The alpha-process elements Mg, Si, and Ca are slightly overabundant [alpha/H]=+0.12. The strong sodium excess, [Na/Fe]=+0.75, is likely to be due to the dredge-up of the matter processed in the NeNa cycle. Heavy elements of the s-process are underabundant relative to the Sun. On the whole, the observed properties of QYSge do not give grounds for including this star into the group of RCrB or RVTau-type type objects.Comment: 29 pages, 8 figures, 4 tables; accepted by Astrophys. Bulleti

Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem.

Rap1 GTPases bind effectors, such as RIAM, to enable talin1 to induce integrin activation. In addition, Rap1 binds directly to the talin1 F0 domain (F0); however, this interaction makes a limited contribution to integrin activation in CHO cells or platelets. Here, we show that talin1 F1 domain (F1) contains a previously undetected Rap1-binding site of similar affinity to that in F0. A structure-guided point mutant (R118E) in F1, which blocks Rap1 binding, abolishes the capacity of Rap1 to potentiate talin1-induced integrin activation. The capacity of F1 to mediate Rap1-dependent integrin activation depends on a unique loop in F1 that has a propensity to form a helix upon binding to membrane lipids. Basic membrane-facing residues of this helix are critical, as charge-reversal mutations led to dramatic suppression of talin1-dependent activation. Thus, a novel Rap1-binding site and a transient lipid-dependent helix in F1 work in tandem to enable a direct Rap1-talin1 interaction to cause integrin activation

The Politics of Commerce : The Congress of Chambers of Commerce of the Empire, 1886-1914

Peer reviewedPublisher PD

Plant genotype influences aquatic-terrestrial ecosystem linkages through timing and composition of insect emergence

Terrestrial leaf litter provides aquatic insects with an energy source and habitat structure,and species differences in litter can influence aquatic insect emergence. Emerging insects also provide energy to riparian predators. We hypothesized that plant genetics would influence the composition and timing of emerging insect communities among individual genotypes of Populus angustifolia varying in litter traits. We also compared the composition and timing of emerging insect communities on litter from mixed genotypes of three cross types of a hybridizing cottonwood complex: P. angustifolia, P. fremontii, and their F1 hybrids. Using litter harvested from an experimental common garden, we measured emerging insect community composition, abundance, and production for 12 weeks in large litter packs affixed with emergence traps. Five major findings emerged. (1) In support of the genetic similarity hypothesis, we found that, among P. angustifolia tree genotypes, litter from more closely related genotypes had more similar litter thickness, nitrogen concentrations, decomposition rates, and emerging insect communities. (2) Genetic similarity was not correlated with other litter traits, although the litter fungal community was a strong predictor of emerging insect communities. (3) Litter decomposition rate, which was the strongest predictor of emerging aquatic insect communities, was influenced by litter thickness, litter N, and the litter fungal community. (4) In contrast to strong community composition differences among P. angustifolia genotypes, differences in community composition between P. fremontii and P. angustifolia were only marginally significant, and communities on F1 hybrids were indistinguishable from P. angustifolia despite genetic and litter trait differences. (5) Mixed litter packs muted the genetic effects observed in litter packs con- sisting of single genotypes. These results demonstrate that the genetic structure of riparian forests can affect the composition and timing of aquatic insect emergence. Because many riparian trees are clonal, including P. angustifolia, large clone size is likely to result in patches of genetically structured leaf litter that may influence the timing and composition of insect emergence within watersheds. Riparian restoration efforts incorporating different tree genotypes could also influence the biodiversity of emerging aquatic insects. Our work illustrates the importance of plant genes for community and ecosystem processes in riparian corridors

Evaluating the impact of befriending for pregnant asylum seeking and refugee women

NoPregnant asylum-seeking and refugee women are a particularly vulnerable group in society, who may be possibly living alone in poverty in inappropriate accommodation (Dunne, 2007) and experiencing hostile attitudes (Hynes and sale, 2010). They may have poor physical and mental health, placing them at an increased risk of poor pregnancy outcomes (National Institute for Health and Care Excellence (NICE), 2010). Despite this, they are less likely to attend for timely maternity care. This article discusses the evaluation to date of an ongoing befriending project located in Northern england, targeting pregnant asylum-seeking and refugee women and helping to address difficulties that they may face. Volunteer befrienders, who themselves are asylum-seeking and refugee mothers, receive training to provide support and guidance to clients. Preliminary data suggest that befriending has advantages for both client and volunteer: clients appear to develop a trusting relationship with their befriender which facilitates self-confidence and helps overcome social isolation; and the volunteers feel that they are undertaking a worthwhile role and often move onto paid employment. Befriending may be a useful resource for midwives and ultimately improve pregnancy outcomes for asylum-seeking and refugee women